The Epstein-Barr virus-induced gene 3 (EBI3; IL27b) product is a novel soluble hematopoietin component related to the p40 subunit (IL12b) of Interleukin 12 (IL12). EBI3 is widely expressed in cells and accumulates in the endoplasmic reticulum and associates with the molecular chaperone calnexin. Besides promoting Th1 cytokine production, EBI3 plays a critical regulatory role in the induction of Th2-type immune responses and the development of Th2-mediated tissue inflammation in vivo, which may be mediated through the control of invariant natural killer (NK) T cell function.
Interleukin 12 was identified and purified from the cell culture media of Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines. Interleukin 12 is a 70 kDa heterodimeric cytokine composed of two disulfide-linked glycoproteins, p40 and p35 (IL12a). Interleukin 12 is primarily produced by macrophages and other antigen-presenting cells. Interleukin 12 has pleiotropic effects in the development of Th1 responses in NK and T lymphocytes, including induction of interferon (INF)-γ production, proliferation, and enhancement of cytotoxic activity, and inhibits Th2 responses.
Multiple, complex and interconnecting mechanisms control discrimination between self and non-self, including the thymic deletion of autoreactive T cells and the induction of anergy in peripheral T cells. In addition to these passive mechanisms, active suppression of autoreactive responder T cells is mediated by regulatory or suppressor T cells. Regulatory T (TR) cells are powerful inhibitors of T cell activation both in vivo and in vitro. Regulatory T cells inhibit autoimmunity and inflammation, maintain immunologic tolerance, and are involved in the induction of tumor antigen tolerance (for reviews, see, Shevach, E. M., Nat. Rev. Immunol. 2:389-400, 2002; Sakaguchi, S., Ann. Rev. Immunol. 22:531-562, 2004; and Mapara and Sykes, J. Clin. Oncology 22:1136-51, 2004).
A major factor limiting immune recognition of cancer cells is the fact that tumors arise from a subject's own tissue and therefore express mainly self antigens to which the subject's T cells have been tolerized, either centrally (i.e., in the thymus) or peripherally. This situation is manifested as tolerance of T cells that display a high avidity for the normal self antigens expressed by the tumor, leaving only functional T cells with low avidity. This problem is exemplified by p53. Because of its high level of expression in certain malignancies, wild-type p53 is a potential target antigen for immunotherapy in a broad spectrum of neoplastic diseases. However, because of low-level expression in normal tissues, T cell tolerance by clonal deletion of high-avidity T cells in the thymus is an obstacle to generating an effective immune response following vaccination with a wild-type p53 antigen (Theobald et al., J. Exp. Med. 185:833-41, 1997). Nevertheless, it is possible to detect and clonally expand T cells specific for tumor-associated antigens (TAA) from tumor-bearing subjects. However, even if TAA-specific cells are present at detectable levels in tumor-bearing subjects, they are often incompetent to reject the tumor (Lee et al., Nat. Med. 5:677-85, 1999).
A number of vaccination approaches are currently being evaluated in clinical trials in efforts to induce host immune responses against a variety of solid tumors (e.g., colon cancer, prostate cancer, melanoma, and renal cell carcinoma). These strategies are all based on the observation that tumors are often poor antigen presenting cells. The lack of costimulatory molecules on their surface and the failure to produce stimulatory cytokines may make them poorly immunogenic and sometimes even tolerogenic. The approaches investigated include the use of gene-modified tumor cells (Soiffer et al., Proc. Natl. Acad. Sci. USA 95:13141-46, 1998), the use of professional antigen presenting cells (e.g., dendritic cells) or dendritic cells fused to tumor cells (Gong et al., Blood 99:2512-17, 2002; Gong et al., Nat. Med. 3:558-61, 1997), and DNA transfer using naked DNA or viral vectors.
Vaccination with dendritic cells has led to systemic T cell responses in treated subjects. However, clinical responses have been less striking, although some patients showed significant antitumor responses, including some complete responses (Nestle et al., Nat. Med. 4:328-32, 1998; Tjoa et al., Prostate 40:125-29, 1999; Murphy et al., Prostate 39:54-59, 1999). Therefore, there remains a need for the development of effective therapies for enhancing antitumor immunity.